Kinase regulation of human MHC class i molecule expression on cancer cells Journal Article

Authors: Brea, E. J.; Oh, C. Y.; Manchado, E.; Budhu, S.; Gejman, R. S.; Mo, G.; Mondello, P.; Han, J. E.; Jarvis, C. A.; Ulmert, D.; Xiang, Q.; Chang, A. Y.; Garippa, R. J.; Merghoub, T.; Wolchok, J. D.; Rosen, N.; Lowe, S. W.; Scheinberg, D. A.
Article Title: Kinase regulation of human MHC class i molecule expression on cancer cells
Abstract: The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8-T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. © 2016 American Association for Cancer Research.
Journal Title: Cancer Immunology Research
Volume: 4
Issue: 11
ISSN: 2326-6066
Publisher: American Association for Cancer Research  
Date Published: 2016-11-01
Language: English
DOI: 10.1158/2326-6066.cir-16-0177
PROVIDER: scopus
PMCID: PMC5110210
PUBMED: 27680026
Notes: Article -- Export Date: 2 May 2017 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Neal Rosen
    351 Rosen
  2. Jedd D Wolchok
    607 Wolchok
  3. Taha Merghoub
    169 Merghoub
  4. Hans David Staffan Ulmert
    48 Ulmert
  5. Scott W Lowe
    144 Lowe
  6. Sadna Budhu
    22 Budhu
  7. Ralph James Garippa
    14 Garippa
  8. James Edward Han
    6 Han
  9. Qing   Xiang
    4 Xiang
  10. Ron Shlomo Gejman
    8 Gejman
  11. Elliott Joseph Brea
    13 Brea
  12. Aaron   Chang
    10 Chang
  13. Claire   Oh
    4 Oh
  14. George   Mo
    2 Mo
  15. Casey   Jarvis
    3 Jarvis